Synapse dysfunction is emerging as a leading cause of neurodevelopmental disorders and many genes that encode for synapse proteins are mutated in these patients. Several rare mutations that affect dendritic spine structure and function have recently been shown to cause ID, while also increasing the risk for developing ASD or epilepsy. While unique combinations of environment and common genetic mutations likely underlie most cases of ID and ASD, mouse models of rare pathogenic mutations offer excellent experimental systems to search for a common pathobiology underlying these disorders. However, it remains largely unknown how developmental synaptic dysfunction resulting from pathogenic mutations impacts circuit function and behavior. This is a particularly important consideration in ID and ASD because these are disorders first diagnosed in young children. Studies that connect developmental synaptic dysfunction to network and behavioral abnormalities are needed to develop new hypotheses that explain the patho-neurobiology of these disorders. These new hypotheses will guide future therapeutic strategies to treat afflicted patients. In this proposal, we aim to understand how dendritic spine synapses are affected by mutations implicated in ID and ASDs. We will perform studies in an emerging mouse model of ID, which provides us with the experimental flexibility to test the idea that abnormal maturation of dendritic spine synapses in neonatal development are driving circuit-level abnormalities that prevent the emergence of normal cognition and behavior. Specifically, we propose that haploinsufficiency of the SYNGAP1 gene, which has recently been shown to cause a form of sporadic ID, induces an early maturation of dendritic spine synapse in periods of postnatal mouse brain development. The early maturation of these excitatory synapses is expected to directly disrupt E/I balance in nascent neural networks, which then impacts key neurodevelopmental milestones, such as the opening of critical period windows of plasticity and supernumerary cortical spine pruning. Our hypothesis predicts that these types of developmental disruptions prevent the acquisition of cognitive and behavioral skills, which could explain both the early onset and persistent nature of these abnormalities in ID patients. Thus, this project Aims to better understand the pathobiology of ID/ASD by linking genetic mutations that disrupt dendritic spine maturation to systems-level processes known to impact the maturation of cognitive and behavioral modalities. It is expected that knowledge gained from these studies will contribute to novel therapeutic strategies to improve the lives of ID patients.